Multicavity [PdnL4]2n+ Cages with Controlled Segregated Binding of

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Multicavity [PdnL4]2n+ cages with controlled segregated binding of different guests Dan Preston, James E. M. Lewis, and James D. Crowley J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11982 • Publication Date (Web): 23 Jan 2017 Downloaded from http://pubs.acs.org on January 23, 2017

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Journal of the American Chemical Society

Multicavity [PdnL4]2n+ cages with controlled segregated binding of different guests Dan Preston,a James E. M. Lewis,a and James D. Crowley*a a

Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand.

ABSTRACT: Multicavity [Pdn(L)4]2n+ metallosupramolecular cages based on long backboned ligands are an attractive approach to increasing molecular size without loss of the binding specificity conferred by small cavity [Pd2(L)4]4+ assemblies. We herein report the synthesis of two double cavity polypyridyl [Pd3(L)4]6+ cages that bind cisplatin [Pt(NH3)2Cl2] within their internal cavities, and interact with triflate (TfO-) on their exohedral faces. We also report the first example of a triple cavity [Pd4(L)4]8+ cage. This cage differs in that the central cavity is phenyl-linked rather than having the pyridyl-core as in the peripheral cavities. The difference in cavity character results in selective guest binding of cisplatin in the peripheral cavities, with triflate binding within the central cavity and on the exohedral faces of the peripheral palladium(II) ions. All the cavities could be simultaneously filled by introducing both cisplatin and triflate concurrently, providing the first example of a discrete metallosupramolecular architecture with segregated guest binding in different designed internal cavities. The ligands and cages were characterised by NMR spectroscopy, mass spectrometry, elemental analysis, and, in one case, X-ray crystallography.

Introduction Using supramolecular interactions, nature is able to selfassemble massive and highly complex structures such as the DNA double helix and folded proteins with an extraordinary degree of fidelity and control. These structures exploit a wide range of molecular recognition events to carry out the processes essential for life. For example, molecular recognition events are responsible for controlling transcription or replication of DNA.1 In a similar fashion molecular recognition events with proteins are exploited for molecular transport,2 storage3 and catalysis,4 as well as being used as a method of intramolecular communication and cellular regulation. Often these molecular recognition processes require the capacity to bind multiple guest molecules simultaneously.5 Since the inception of metallosupramolecular chemistry, workers have been inspired by nature to create discrete metal-containing architectures6 of ever increasing complexity and size.7 The cavities of these architectures have been exploited for molecular recognition and systems designed to bind a wide range of guests including reactive molecules and intermediates,8 pollutants9 and drugs.10 These impressive results have mostly been achieved using relatively small metallosupramolecular architectures that can only bind one guest molecule. Where the cage architecture has been large enough to encapsulate more than one guest molecule often the binding event remains homoleptic and multiple copies of the same guest are captured.11 In order to increase the sophistication and applications of these metallosupramolecular architectures, systems that are able to selectively bind multiple different guests molecules are required. This has been achieved in

some examples and has enabled the use of metallosupramolecular architectures as molecular reaction flasks12 and catalysts.13 However, while these examples show the potential of these architectures the discovery of systems that are able to binding two (or more) different guest molecules is often carried out by trial–and-error rather than design.14 Indeed the design of metallosupramolecular architectures that are able to bind two (or more) different guests selectively is not simple. [Pd2(L)4]4+ cages,15 in particular those assembled using pyridyl ligands, have become one of the most common class of metallosupramolecular architectures and have been shown to display wide ranging molecular recognition properties.16 These [Pd2(L)4]4+ assemblies have been exploited for binding diverse guests, such as fullerenes,17 radical initiators,8b metal complexes16f, 18 and anions.19 However, these [Pd2(L)4]4+ systems are small and for the most part can only bind up to two guest molecules.15-16 Fujita and coworkers have generated a series of related larger hollow [Pdn(L)2n]2n+ complexes, where n equals 6, 12, 24 or 30, using bent bis-pyridine ligands and square planar Pd(II) ions (Figure 1a).20 These larger [Pdn(L)2n]2n+ species possess large cavities that could, in principle, be used to bind a large number of guest molecules. However, in practice, the parent unfunctionalised species have displayed rather limited molecular recognition properties presumably because they have large, undefined cavities with large portals that allow facile, rapid exchange of the guest molecules from the internal space to the external environment. In contrast to the smaller [Pd2(L)4]4+ systems there are no examples of the larger unfunctionalised [Pdn(L)2n]2n+ species binding neutral guest molecules and only a few examples of binding anionic guests through strong ion-ion

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interactions.21 In order to “turn on” guest binding in these larger systems the cavities have to be endo-functionalised with binding units that enhance molecular recognition events.7a, 22 Neutral organic guests such as nile red,23 C60,24 naphthalenediimide,24 1-pyrenecarboxaldehyde25 and even cationic cyclobis-(paraquat-p-phenylene) macrocycles,26 have been bound with these endo-functionalised system. However, the endo-functionalisation also reduces the size of the cavity.27 Therefore, simply increasing the size of the cage cavity of the metallosupramolecular architecture does not automatically lead to systems that will bind more guest molecules. In most cases additional functionalization of the large single cavity is required to overcome the loss of multiple short-contact supramolecular interactions that are required for binding specificity. An alternative approach to binding multiple different guest molecules selectively within a single metallosupramolecular architecture is to design systems that feature several smaller cavities within a larger self-assembled complex. These types of multicavity metallosupramolecular architectures remain rare. Lehn and coworkers reported heteroleptic copper(I) complexes with oligo-pyridyl ligands and hexaphenylhexaazatriphenylene to give double- and triple-cavity structures, capable of anion binding.28 Bosnich and co-workers have generated selfassembled rectangles and trigonal prisms that display two or three molecular clefts capable of binding polyaromatic hydrocarbons29 and planar metal complexes.30 Several groups31 have generated multicavity assemblies through interpenetration of discrete [Pd2(L)4]4+ cages or other Pd(II) assemblies,32 giving catenated, multicavity products. However, in most of these cases the multicavity metallosupramolecular architectures have only been shown to interact with multiple copies of the same guest molecule. In 2002 McMorran and Steel,33 building on their pioneering work on [Pd2(L)4]4+ cages,34 proposed that pseudo-linear polypyridyl ligands could be exploited to generate tube-like metallosupramolecular architectures which feature multiple cavities of identical size and shape to that of the parent [Pd2(L)4]4+ cage (Figure 1b).

2n+

Figure 1. a) Cartoon representation of the [Pdn(L)2n] series of cages synthesised by Fujita and coworkers where n = 6, 12, 24 or 30 with increasing cavity size and b) linearly extending cages with constant cavity size.

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Building on our own work with [Pd2(L)4]4+ cages, herein we report the synthesis of pseudolinear penta- and hexa-pyridyl ligands. These ligands are exploited to generate tube-like36 double37 and triple cavity metallosupramolecular architectures. Additionally, the molecular recognition properties of these multicavity architectures remain unchanged. We have previously reported a [Pd2(L)4]4+ cage (C1) based on a 2,6-bis(pyridin-3ylethynyl)pyridine ligand (L1), which binds two molecules of the anti-cancer drug cisplatin (diamminedichloroplatinum(II)) within the cavity.18c The double cavity systems (C2, C2peg, Scheme 1a) retain the molecular recognition properties of the parent cage but are able to bind twice as much of the guest. The corresponding triple cavity system (C3peg, Scheme 1a) contains two different types of cavity. The two terminal cavities are pyridyl lined like the parent C1 cage but the central cavity is different and is linked by a 1,3-disubstituted phenyl spacer unit. Titration experiments confirm that these two different cavities are able to selectively bind different guest molecules, demonstrating that these multicavity metallosupramolecular architectures are able to selectively encapsulate multiple different guest molecules in different pockets of the host architecture. 18c, 19a, 35

Synthesis and Characterisation The polypyridyl ligands L2, L2peg and L3peg (Scheme 1) were synthesised (yields of 71%, 49%, and 70% respectively) via sequential Sonogashira couplings (Supporting Information, Scheme S1.1) using methods analogous to those already reported.18c, 35d Due to the low solubility of L2 (and its C2 cage, vide infra) the synthesis of the hexapyridyl analog without PEG solubilising groups was not attempted. The composition of the ligands was confirmed using elemental analysis, high resolution electrospray ionisation mass spectrometry (HR-ESMS) and 1H and 13C nuclear magnetic resonance (NMR) spectroscopy (Supporting Information, Figures S1.1-1.12). The cages (C2, C2peg, and C3peg) were assembled by heating d6-DMSO solutions of [Pd(CH3CN)4](BF4)2 (3 or 4 equiv.) and the corresponding ligand (L2, L2peg or L3peg (4 equiv.)) at 50 – 70° C for 3 – 8 hours (Scheme 1a). These conditions were different to those required for the formation of the parent [Pd2(L)4]4+ cages (C1 and C1peg18c, 35d) which are instantaneously assembled at room temperature in either acetonitrile, DMF or DMSO. Presumably the highly coordinating DMSO solvent and the longer reaction times at elevated temperatures are required to facilitate the self-correction process and allow the formation of the tube-like systems. The cages (C2, C2peg, and C3peg) were characterized using 1H, 13C and DOSY NMR spectroscopies, HR-ESMS and elemental analysis (Supporting Information, Figures S1.13-1.21 and S2.1 and 2.2). The 1H NMR spectra of the cages (C2, C2peg, and C3peg) display a single set of signals, all shifted downfield relative to the free ligand (Figure 2a and b, Supporting Information, Figures S1.13, 1.16, 1.19 and S2.1). The signals corresponding to those protons


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adjacent to the nitrogen atoms of the coordinating pyridyl rings were most significantly shifted (Δδ = 0.80-0.50 ppm for Ha, Hb, Hg, Hh and Hi) (Figure 2a and b and Supporting Information, Figure S2.1).

1

H DOSY NMR spectra of the cages (C2, C2peg, and C3peg) were consistent with the formation of a single metallosupramolecular architecture in solution (Supporting Information, Figure S2.2 and Table S2.1). Comparison of the cage diffusion coefficients (D, × 10-10 m2 s-1) to those of the corresponding ligands (DL2 = 1.88, DL2peg = 1.43, DL3peg = 1.41, DC2 = 0.80, DC2peg = 0.66, DC3peg = 0.62) showed an approximately 2:1 ratio, consistent with results previously obtained for the parent [Pd2(L)4]4+ cages (C1 and C1peg18c, 35d). The diffusion coefficient of C3peg is smaller than those observed for C2 and C2peg consistent with the larger size of the triple cavity cage and a plot of log(D) against log(MW) for ligands and complexes gave a good linear fit (Supporting Information, Figure S2.2). HR-ESMS, under pseudo-coldspray conditions,38 provided further support for the formation of the tubelike cages, (Figure 2f, Supporting Information, Figures S1.15, 1.18 and 1.21). While the spectra were complicated by varied types and number of anions (formate (HCO2−), chloride (Cl-) and tetrafluoroborate (BF4-)), associated under mass spectrometry conditions, a series of isotopically resolved peaks consistent with the presence of the polycationic complexes [Pd3(L2 or L2peg)4(X)6-n]n+ and [Pd4(L3peg)4(X)6-n]n+ (where X = HCO2−, Cl- or BF4- and n = 6, 5, or 4) were observed and de-convoluted (Supporting information, Figures S1.15).

1

Scheme 1, a) Synthesis of multicavity cages C2, C2peg, and C3peg. Conditions: (i) [Pd(CH3CN)4](BF4)2, d6-DMSO, 50-80 °C , 3-8 h, b) C3peg exhibits selective binding of cisplatin in peripheral cavities (top) and triflate in the central cavity and exohedral faces (bottom), with all binding sites occupied in the presence of both guests.

Figure 2. Partial H NMR spectra (CD3CN, 298 K, 400 MHz) of a) L2peg, b) C2peg c) (cisplatin)4⊂C2peg, d) (triflate)2⊂C2peg, e) (cisplatin)4(triflate)2⊂C2peg and f) partial HR-ESI mass spectrum (DMSO/CH3CN) of C3peg, showing observed isotopic distributions in black above and calculated distributions in colour below.



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Additionally, X-ray diffraction-quality crystals were also obtained of C2 through vapour diffusion of diethyl ether into a DMF solution of the cage. The structure was solved in the triclinic space group P1. This revealed the anticipated discrete structure with four ligands joined together by three palladium(II) ions giving the desired [Pd3(L)4]6+ assembly architecture with pseudo-D4h symmetry (Figure 3, Supporting Information, Figure S3.1 and S3.2 and Tables S3.1 and S3.3). Crystallographically the two cavities of the assembly are related by symmetry through a centre of inversion through Pd2, and are therefore identical. Two molecules of DMF were found within each of the cavities. The oxygen atoms of the solvent molecules are engaging in quadfurcated hydrogen bonding to the internally directed Ha and Hg hydrogen atoms of the cage. The individual cavities are of similar dimensions to the parent system C1,18d with the distance between the nearest palladium(II) ions (Pd1---Pd2) being 11.75 Å, and the distance between opposing endohedral pyridyl nitrogen atoms being 10.72 (N2---N4) and 10.77 Å (N42---N44). The distance between the terminal (ter) palladium(II) ions (Pd1---Pd1') was thus found to be double that between the central and terminal ions, at 23.51 Å.

(SPARTAN16, MMFF, Supporting Information, Figure S3.3) indicated that the tricavity system was approximately 3.5 nm in length (Pdter---Pdter distance), similar to what would be predicted from the solid state structures of C1 and C2.

Host-guest chemistry With the structures of these multicavity architectures confirmed we examined the molecular recognition properties of these new systems. The host-guest behavior of the parent [Pd2(L)4]4+ cage C1 (generated from 2,6bis(pyridin-3-ylethynyl)pyridine ligand L1) is somewhat limited due to the small size of the cavity. However, we18c, 35a, d, g, h and others39 have shown that C1 and related systems will bind two molecules of cisplatin within the central cavity. We have also shown that C1 will encapsulate certain anions (nitrate, NO3- and mesylate, MsO-) but not others (toslyate, TsO-, triflate, TfO-, hexafluoroantimonate, SbF6-).19a Hooley et al. 19b, 40 and Lusby and coworkers41 have shown that related cages C1Phenyl that have a central 1,3-disustitued phenyl spacer unit rather that a 2,6-substituted pyridyl core are able to binding both neutral organic and anionic (TfO-) guest molecules. Thus we have used cisplatin and triflate guests to examine the host-guest behaviour of the multicavity cages (C2, C2peg, and C3peg). 1

Figure 3. Tube representation of the crystal structure of (DMF)4⊂C2. Counterions omitted for clarity. Colours: Cage carbon grey, DMF carbon black, hydrogen white, nitrogen blue, palladium magenta. Bond lengths/interatomic distances (Å): Pd1-N1 2.005(5), Pd2-N3 2.004(5), Pd1'-N5 2.009(5), N2---N4' 10.72(1), Pd1---Pd2 11.7530(6), Pd1---Pd1' 23.506(1).

Thus the dicavity cages C2 and C2peg (SPARTAN16, MMFF, Supporting Information, Figure S3.3) are 2.3 and 2.4 nm in length (Pdter---Pdter distance) and while we could not confirm the molecular structure of the C3peg cage using crystallography, molecular modeling

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H NMR experiments indicated that the double cavity systems (C2 and C2peg) retain the cisplatin binding ability of the parent cages. While cisplatin was essentially completely insoluble in CD3CN, addition of cisplatin to CD3CN solutions of one of the double cavity cages (C2 and C2peg) resulted in dissolution of the cisplatin, providing strong evidence that the cisplatin guest molecule is taken up by and complexed within the cages (Scheme 1b). 1H NMR spectroscopy (CD3CN) of the resulting mixtures further supported the postulate that the cisplatin was bound within the double cavity cages. The addition of cisplatin to C2 or C2peg in CD3CN brought about downfield shifts and broadening of the proton resonance due to the internally directed protons ortho to the coordinating nitrogen atoms (Ha and Hh for C2 and Ha and Hg for C2peg) (Figure 2c, Supporting Information, Figure s4.1). For the cisplatin⊂C2peg host-guest adduct the Ha and Hg proton resonances were shifted by 0.10 and 0.15 ppm, respectively, while all the other proton resonances of the host cage were essential unaffected by the presence of cisplatin in solution indicating that the cisplatin guest molecules are bound within the cavities of the host. Unfortunately, the effective insolubility of cisplatin in CD3CN precluded the use of a mole ratio titration29a, 35d, 42 to confirm the encapsulation of four cisplatin molecules. However, given that it is well established18c, 35d, h that the parent cages can bind two molecules of cisplatin and the X-ray structure (Figure 3) of C2 contains four molecules of DMF, it is presumed that the host-guest adducts formed are (cisplatin)4⊂C2 and (cisplatin)4⊂C2peg respectively (Figure 2).


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The interaction of the anionic guest TfO- with the more soluble C2peg cage in CD3CN was also examined using NMR spectroscopy (Supporting Information, Figures s4.2 and S4.3). The introduction of [NBu4]OTf (2 equivalents) to a CD3CN solution of the cage at 298 K resulted in a downfield shift of the cage’s exohedral proton Hb (Δδ = 0.13 ppm, Figure 2d, Supporting Information, Figure s4.2), indicative of interactions with the TfOguests on the exterior faces of the cage. No other notable shifts in the 1H NMR spectrum were observed. Importantly, there were no shifts in the endohedral Ha and Hg protons which indicated that there was no encapsulation of the TfO- anions in the internal cavities. Complexationinduced shifts were also observed in the 19F NMR spectra (Supporting Information, Figure S4.3). The fluorine resonance of the TfO- anions was shifted downfield from the chemical shift of “free” TfO- due to the interaction with the cage. At the same time the chemical shift of the BF4anions was shifted upfield (relative to its position in the C2peg complex spectrum) as it is displaced from the cage. These data are consistent with the TfO- anions displacing associated BF4- anions from the outside face of the cage. A titration of [NBu4]OTf into a CD3CN solution of the C2peg cage in CD3CN was monitored via 1H and 19F NMR spectroscopies. Examining the shifts in the peaks belonging to Hb, Ftriflate and FBF4 using the mole-ratio method confirmed 1:2 binding between the cage and TfO- anions (Supporting Information, Figure s4.4). Curve fitting the titration data using the 2:1 binding models (Supporting Information, Figures s4.4 and S4.5, www.supramolecular.org) suggested that the binding constants for the host-guest interaction were K1 = 4800 ± 400 -1 and K2 = 20 ± 10 M ,43 values similar to those of related 35d, 44 host-guest systems. These NMR experiments indicated that the C2peg cage binds two TfO- anions on the outside faces of the dicavity architecture. This behavior is similar to that observed with the parent C1 cage and TfOanions.19a The lack of interaction between the TfO- anions and the central cavities of the cage can be attributed to the unfavourable lone pair-lone pair interactions between the lone pairs of electrons of the internally facing nitrogen atoms of the pyridyl linkers lining the cavities with the lone pairs of the fluorine atoms of the CF3 group.19a NMR experiments also confirmed that the C2peg cage can interact with both cisplatin and TfO- guest simultaneously in CD3CN. Addition of cisplatin (10 eq.) and triflate (2 eq.) to a solution of the cage in CD3CN brought about downfield shifts of Ha, Hb and Hg, confirming interaction with both guests concurrently (Figure 2e) forming a [(cisplatin)4(triflate)2⊂C2peg]4+ host-guest adduct where cisplatin fills the cavities and TfO anions bind on the terminal faces of the metallo-tube. We have previously observed the formation of a similar adduct between cisplatin, MsO- and the C1peg cage.35d The design of the tricavity C3peg system offers the potential for simultaneously binding two different guests selectively in the different cavities of the cage. While the size of the cavities in the C3peg system are all identical the two terminal cavities are lined with pyridyl

units whereas the central cavity contains phenyl moieties (Scheme 1). The 1H NMR spectrum of a mixture of cisplatin and C3peg in CD3CN at room temperature was consistent with selective binding of cisplatin in the terminal cavities of the cage. Addition of cisplatin to C3peg resulted in downfield shifts of the internally directed α-pyridyl protons of the peripheral cavities only (Figure 4a and b, Δδ(Ha) = 0.07 ppm, Δδ(Hg) = 0.09 ppm). There were no shifts in the peaks pertaining to the protons internally directed into the central cavity (Hi and Hl), indicating that cisplatin guests were not encapsulated in this cavity. These finding are consistent with our previous results with the parent cages C1 and C1Ph which had shown that encapsulation within the cages’ cavity is dependent on the key hydrogen–bonding interaction between the amines of the two bound cisplatin molecules and the noncoordinating pyridyl nitrogen atoms within the cage architecture.18c

1

Figure 4. Partial H NMR spectra (CD3CN, 298 K, 400 MHz) of a) C3peg, b) (cisplatin)4⊂C3peg, c) (triflate)3⊂C3peg, and d) (triflate)3(cisplatin)4⊂C3peg.

In contrast, treatment of a room temperature CD3CN solution of C3peg with three equivalents of [NBu4]OTf resulted in a downfield shift in the triflate peak in the 19F spectrum (Δδ(F) = 0.3 ppm, Supporting Information, Figure S4.8) compared to free [N(Bu)4](OTf). The chemical shift of the fluorine peak pertaining to BF4- shifted upfield from that of the free host (Δδ(F) = 0.3 ppm), suggesting displacement of BF4by triflate. The corresponding 1H NMR spectrum showed no shifts of the peaks belonging to internal protons of the terminal cavities Ha and Hg (Figure 4c, and Supporting Information, Figure S4.9). However, shifts of protons on the outside face (Hb) and inside the central cavity (Hi) of the tricavity cage were observed (Δδ(Hb) = 0.13 ppm, Δδ(Hi) = 0.05 ppm, Figure 4c, and Supporting Information, Figure S4.9). These results indicate selective encapsulation of the triflate anions within the central cavity and interaction with exohedral faces of the terminal palladium(II) ions, with no encapsulation in the outer cavi-



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ties. Titration of triflate into a solution of the cage in CD3CN using the mole ratio method and 1H and 19F NMR spectroscopies (Supporting Information, Figure S4.10), monitoring the change in chemical shift of Hb, Hi, Ftriflate and FBF4 indicated that three triflate guests interacted with each cage, suggesting that two anions interact with the terminal faces of the tube in a similar fashion to what was observed with C2peg while the third guest is contained in the central cavity.45 This postulate is consistent with the smaller downfield shift of proton Hi, as only one palladium(II) metal ion and associated Hi protons can interact with the sulfonate group at one time. When excess cisplatin and triflate are simultaneously introduced to a CD3CN solution containing the tricavity cage, downfield shifts of Ha, Hb, Hg and Hl are observed indicative of guests binding in each of the cage cavities and on the outside faces of the architecture. These results are consistent with the formation of a [(cispla5+ tin)4(triflate)3⊂C3peg] host-guest adduct and suggested that C3peg was able to concurrently bind of two distinct guests selectively within the different cavities of the host architecture (Figure 4d). To obtain further insight into the guest selectivity of the different cage cavities DFT calculations (gas phase, B3LYP with the LANL2DZ basis set for palladium atoms and the 6-31G(d) basis set for all other atoms, Supplementary Information, 5. DFT calculations) were carried out to determine the minimized energies for the “empty” cages (CH3CN)2⊂C1, and (CH3CN)2⊂ C1phenyl) and the guest containing cages ((triflate)(CH3CN)⊂C1, (triflate)(CH3CN)⊂C1phenyl, (cisplatin)2⊂C1) and (cisplatin)2⊂C1phenyl). The energy of guest binding (ΔE) for each cage system was then calculated using Hess’s Law (products - reactants, equation S1, Supplementary Information). The calculation showed that the host-guest interaction of cisplatin with the C1 cage was 30.8 KJ mol-1 more favorable than with the C1phenyl cage. Conversely, host-guest interaction of triflate with the C1phenyl cage was 61.1 KJ mol-1 more favorable than the same interaction with the C1 cage (Supplementary Information, Figure S5.1). Furthermore the results of the calculations were completely consistent with the observed experimental binding selectivities. In the case of the cisplatin-cage adducts the reasons for the observed binding selectivity is obvious. The C1phenyl cage is missing the four important central pyridyl----NH3 hydrogen bonding interactions that are observed in the all solid state structures of the various (cisplatin)2⊂C1 adducts.18c, 35h, 39 The reasons why triflate prefers to bind in the C1phenyl cage appear to be more subtle. However, we have previously attributed this to unfavourable lone pair-lone pair interactions between the lone pairs of electrons of the internally facing nitrogen atoms of the pyridyl linkers lining the cavities with the lone pairs of the fluorine atoms of the CF3 group and sulfonate oxygen atoms.19a Electrostatic potential maps of the calculated triflate cage adducts provide additional support for this postulate (Supplementary Information, Figure S5.2).

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Conclusions A series of pseudo-linear penta- and hexa-pyridyl ligands (L2, L2peg and L3peg) were synthesized and combined with Pd(II) ions to create multicavity tube-like extended cages. The pentapyridyl ligands (L2 and L2peg) gave the double cavity cages C2 and C2peg which feature pyridyl cores within the cage cavities. These systems retained the molecular recognition properties of the parent C1 and C1peg cages and were shown to encapsulate four molecules of cisplatin within the two cavities and bind two triflate anions on the terminal exterior faces of the host. The hexapyridyl ligand L3peg was used to form the first example of a multicavity cage of this sort with three cavities, C3peg. Additionally, the central cavity differed from the peripheries in that it had a phenyl spacer unit. This gave rise to two distinct cavity environments which could be exploited to give selective guest binding. It was shown using NMR experiments that the only the peripheral pyridyl-core cavities bound cisplatin, while triflate guests could be bound within the phenyl lined central cavity and on the terminal exohedral faces of the assembly. No interaction of cisplatin with the central cavity nor triflate with the peripheral cavities was observed. Thus the multiple binding sites within the tricavity cage could engage in simultaneous segregated guest binding of the cisplatin and triflate guests. To the best of our knowledge this is the first example of a discrete metallosupramolecular structure with differentiated internal cavities and the capacity for internal discrimination of guests between cavity types.46 Assemblies with the capacity to concurrently bind more than one guest have been reported previously only for single-cavity systems where the guests are bound in the same cavity space,12b-d, 12f, 14a, c, 18a, 47 or for catenated coordination cages with pockets capable of differentiated anion/anion or anion/neutral guest binding.31d, e, j Here we have shown that ligand design can be exploited to generate metallosupramolecular hosts with multiple discrete binding sites that can be used for selected encapsulation of different guests. While the current tricavity system is only a proof-of–principle design the ability to sequester different guests within segregated compartments of a single discrete metallosupramolecular structure could be highly advantageous in numerous potential applications, including dual guest (drug) delivery, and controllable enzyme-like multi-component reactions and catalysis.

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Experimental details, H, C and DOSY NMR and ESMS spectral information, and X-ray crystallography and molecular modelling files. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected].


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Author Contributions All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT DP and JEML thank the University of Otago for PhD scholarships. The authors thank the Department of Chemistry, University of Otago for additional funding. The authors acknowledge the contribution of the NeSI high performance computing facilities to the results of this research. New Zealand’s national facilities are provided by the New Zealand eScience Infrastructure and funded jointly by NeSI’s collabrator institutions and through the Ministry of Business, Innovation & Employment’s Research Infrastructure program. URL: https://www.nesi.org.nz.

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40. Johnson, A. M.; Moshe, O.; Gamboa, A. S.; Langloss, B. W.; Limtiaco, J. F. K.; Larive, C. K.; Hooley, R. J., Inorg. Chem. 2011, 50 (19), 9430-9442. 41. August, D. P.; Nichol, G. S.; Lusby, P. J., Angew. Chem., Int. Ed. 2016, 55 (48), 15022-15026. 42. Meyer, A. S., Jr.; Ayres, G. H., J. Am. Chem. Soc. 1957, 79, 49-53. 43. (a) www.supramolecular.org (accessed 10th October 2016); (b) Brynn Hibbert, D.; Thordarson, P., Chem. Commun. 2016, 52 (87), 12792-12805. 44. Bloch, W. M.; Abe, Y.; Holstein, J. J.; Wandtke, C. M.; Dittrich, B.; Clever, G. H., J. Am. Chem. Soc. 2016, 138 (41), 13750–13755.

45. A calculation of binding constants was precluded by the presence of different binding sites within C3peg for triflate and the number of variables that would need to be fitted. 46. Systems which bind different guest within the central cavity and on the ousitde faces of the architecture are known see; (a) Rizzuto, F. J.; Wu, W.-Y.; Ronson, T. K.; Nitschke, J. R., Angew. Chem., Int. Ed. 2016, 55 (28), 7958-7962; (b) Ramsay, W. J.; Nitschke, J. R., J. Am. Chem. Soc. 2014, 136 (19), 7038-7043. 47. Kusukawa, T.; Nakai, T.; Okano, T.; Fujita, M., Chem. Lett. 2003, 32 (3), 284-285.



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SYNOPSIS TOC


10

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87x47mm (220 x 220 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

170x227mm (96 x 96 DPI)


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50x96mm (220 x 220 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

201x158mm (96 x 96 DPI)


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78x198mm (220 x 220 DPI)



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82x33mm (296 x 296 DPI)


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Multicavity [PdnL4]2n+ Cages with Controlled Segregated Binding of

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